Contents

Mechanism

Unlike brain trauma that occurs due to direct impact and deformation of the brain, DAI is the result of traumatic shearing forces that occur when the head is rapidly accelerated or decelerated, as may occur in auto accidents, falls, and assaults.[8] It usually results from rotational forces or severe deceleration.[9][10] Vehicle accidents are the most frequent cause of DAI; it can also occur as the result of child abuse[11] such as in shaken baby syndrome.[12]

The major cause of damage in DAI is the disruption of axons, the neural processes that allow one neuron to communicate with another. Tracts of axons, which appear white due to myelination, are referred to as white matter. Acceleration causes shearing injury, which refers to damage inflicted as tissue slides over other tissue. When the brain is accelerated, parts of differing densities and distances from the axis of rotation slide over one another, stretching axons that traverse junctions between areas of different density, especially at junctions between white and grey matter.[2] Two thirds of DAI lesions occur in areas where grey and white matter meet.[2]

Histological characteristics

DAI is characterized by axonal separation, in which the axon is torn at the site of stretch and the part distal to the tear degrades. While it was once thought that the main cause of axonal separation was tearing due to mechanical forces during the trauma, it is now understood that axons are not typically torn upon impact; rather, secondary biochemical cascades, which occur in response to the primary injury (which occurs as the result of mechanical forces at the moment of trauma) and take place hours to days after the initial injury, are largely responsible for the damage to axons.[3][8][15]

Though the processes involved in secondary brain injury are still poorly understood, it is now accepted that stretching of axons during injury causes physical disruption to and proteolytic degradation of the cytoskeleton.[1] It also opens sodium channels in the axolemma, which causes voltage-gated calcium channels to open and Ca2+ to flow into the cell.[1] The intracellular presence of Ca2+ unleashes several different pathways, including activating phospholipases and proteolytic enzymes, damaging mitochondria and the cytoskeleton, and activating secondary messengers, which can lead to separation of the axon and death of the cell.[8]

Cytoskeleton disruption

Axons are normally elastic, but when rapidly stretched they become brittle, and the axonal cytoskeleton can be broken. It is thought that integrins connected to the extracellular matrix outside the cell and to the cytoskeleton within it can transmit forces from the matrix to the cytoskeleton [16] and cause the latter to tear when the axon is stretched.[17]

Misalignment of cytoskeletal elements after stretch injury can lead to tearing of the axon and death of the neuron. Axonal transport continues up to the point of the break in the cytoskeleton, but no further, leading to a buildup of transport products and local swelling at that point.[18] When it becomes large enough, swelling can tear the axon at the site of the break in the cytoskeleton, causing it to draw back toward the cell body and form a bulb.[6] This bulb is called a retraction ball, the hallmark of diffuse axonal injury.[2]

When the axon is transected, Wallerian degeneration, in which the part of the axon distal to the break degrades, takes place within one to two days after injury.[19] The axolemma disintegrates,[19] myelin breaks down and begins to detach from cells in an anterograde direction (from the body of the cell toward the end of the axon),[20] and nearby cells begin phagocytic activity, engulfing debris.[21]

Calcium influx

While sometimes only the cytoskeleton is disturbed, frequently disruption of the axolemma occurs as well, causing the influx of Ca2+ into the cell and unleashing a variety of degrading processes.[19][22] An increase in Ca2+ and Na+ levels and a drop in K+ levels is found within the axon directly after injury.[8][19] Possible routes of Ca2+ entry include sodium channels, pores torn in the membrane during stretch, and failure of ATP-dependent transporters due to mechanical blockage or lack of energy.[8] High levels of intracellular Ca2+, the major cause of post-injury cell damage,[23] destroy mitochondria,[6] contribute to the generation of reactive oxygen species[15] and trigger phospholipases and proteolytic enzymes that damage Na+ channels and degrade or alter the cytoskeleton and the axoplasm.[24][19] Excess Ca2+ can also lead to damage to the blood brain barrier and swelling of the brain.[23]

Generally occurring one to six hours into the process of post-stretch injury, the presence of calcium in the cell initiates the caspase cascade, a process in cell injury that usually leads to apoptosis, or "cell suicide".[25]

Diagnosis and treatment

DAI is difficult to detect since it does not show up well on CT scans or with other macroscopic imaging techniques, though it shows up microscopically.[2] However, there are characteristics typical of DAI that may or may not show up on a CT scan.[3] Diffuse injury has more microscopic injury than macroscopic injury and is difficult to detect with CT and MRI, but its presence can be inferred when small bleeds are visible in the corpus callosum or the cerebral cortex.[27] MRI is more useful than CT for detecting characteristics of diffuse axonal injury in the subacute and chronic time frames.[28] Newer studies such as Diffusion Tensor Imaging are able to demonstrate the degree of white matter fiber tract injury even when the standard MRI is negative. Since axonal damage in DAI is largely a result of secondary biochemical cascades, it has a delayed onset, so a person with DAI who initially appears well may deteriorate later. Thus injury is frequently more severe than is realized, and medical professionals should suspect DAI in any patients whose CT scans appear normal but who have symptoms like unconsciousness.[2]

MRI is more sensitive than CT scans,[3] but MRI may also miss DAI, because it identifies the injury using signs of edema, which may not be present.[26]

DAI is classified into grades based on severity of the injury. In Grade I, widespread axonal damage is present but no focal abnormalities are seen. In Grade II, damage found in Grade I is present in addition to focal abnormalities, especially in the corpus callosum. Grade III damage encompasses both Grades I and II plus rostralbrain stem injury and often tears in the tissue.[29]

DAI currently lacks a specific treatment beyond what is done for any type of head injury, including stabilizing the patient and trying to limit increases in intracranial pressure (ICP).

Potential Treatments

Polyethylene glycol acts as a membrane sealant, and may serve to prevent the aforementioned devastating calcium influx. Rats treated with polyethylene glycol immediately following DAI induction showed no cytotoxic edema on diffusion weighted MRI 7 days later unlike controls.[30]

History

The idea of DAI first came about as a result of studies by Sabina Strich on lesions of the white matter of individuals who had suffered head trauma years before.[31] Strich first proposed the idea in 1956, calling it diffuse degeneration of white matter, however the more concise term "Diffuse Axonal Injury" was eventually preferred.[32] Strich was researching the relationship between dementia and head trauma[31] and asserted in 1956 that DAI played an integral role in the eventual development of dementia due to head trauma.[11] The term DAI was introduced in the early 1980s.[33]